This project is designed to provide information on basic neural mechanisms involved in the generation and control of respiratory movements in mammals. The long-range goal is to explain the ontogeny and neurogenesis of respiratory movements in terms of the molecular, biophysical, synaptic, and network properties of respiratory neurons in the mammalian brainstem and spinal cord. Current work focuses on cellular and network mechanisms generating the respiratory rhythm in the brainstem. A set of interrelated, multidisciplinary studies are ongoing to determine: sites, cellular components, and architecture of brainstem networks involved in generation and transmission of respiratory rhythm; biophysical properties and synaptic interactions of rhythm-generating neurons; and neurochemical mechanisms for modulation and synaptic transmission of rhythm. Experiments are performed with isolated in vitro brainstem-spinal cord and brainstem slice preparations from fetal, neonatal, and juvenile rodents. The critical brainstem locus containing the populations of neurons generating the rhythm has been identified. Novel in vitro slice preparations containing this critical region and functionally active respiratory networks have been developed and are used for experimental analysis of mechanisms concurrently at cellular and network levels. Computational approaches are being used in parallel to experimental studies to model respiratory neurons and networks. A first generation of computational models of the respiratory oscillator have been developed, based on available data of neuron biophysical properties and network architecture in the neonatal and adult brainstem. Simulations with these models are able to mimic many features of the oscillatory behavior of brainstem respiratory neurons found with intracellular recordings in the neonatal system in vitro and the adult nervous system in vivo. These models are currently being applied to explore principles of design and control of the respiratory oscillator at different stages of nervous system development.